Certificate of correction



United States Patent 3,124,573 Z-FORMYL CORTICGIDS Albert Bowers and John Edwards, Mexico City, Mexico, assignors, by mesne assignments, to Syntax Corporation, a corporation of Panama N0 Drawing. Filed Dec. 4, 1961, Ser. No. 156,958 21 Claims. (Cl. 26ll--239.55)

The present invention relates to novel cyclopentanophenanthrene derivatives and to a process for the production thereof.

More particularly the present invention relates to 2- formyl-A -derivatives of cortical hormones.

The novel compounds of the present invention are represented by the following formulas:

In the above formulas X represents S-hydroxy or keto; Y represents hydrogen, fluorine or chlorine; Z represents hydrogen, fluorine, chlorine or methyl; R represents hydrogen, 16u-methyl, 16f3-rnethyl or the group OR in the 16a-position', R represents hydrogen or an acyl group. The acyl group is derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t butylacetate, phenoxyacetate, cyclopentylpropionate, aminoaceate and fl-chloropropionate. R and R represent the residue of a hydrocarbon of up to 8 carbon atoms of straight, branched, cyclic or mixed aliphatic-cyclic chain, saturated or unsaturated including aromatic groups.

The compounds represented by the above formulas have high anti-inflammatory properties and also exhibit glucocorticoid, thymolytic and anti-estrogenic activities with low incidence of side efiects. These compounds are not ulcerogenic and do not give rise to psychoses or stimulate appetite.

The novel compounds of the present invention are 2 prepared by the process illustrated by the following equation:

CHSOR! O-GH2 0-0-0 5 i...oH H01 1 B no? NWR 10 1) (11) Z Z 15 l 0-CH2 0-0112 O C1; O O-C-O H J J 110-0: v) 0:

CHQO R CH2O R1 W011 IW p NVVR 110 MR w I O O I ll (VII) 5 Z i Z (EH 0 K 0 0 adj (VIII) In the above formulas, R, R and Z have the same meaning as previously set forth; W represents fluorine or chlorine.

In practicing the process outlined above, the starting compound which is a hydrocortisone derivative (I; R ;=H) is treated with formaldehyde in the presence of an acid such as hydrochloric acid to furnish the 17,20';20,21-bismethylenedioxy derivative thereof (II). This derivative is treated with ethyl formate in the presence of an alkali metal hydride, such as sodium hydride in a solvent inert to the reagent, preferably benzene; the organic sodium salt thus formed is hydrolyzed in an acid medium such as dilute hydrochloric acid, yielding the corresponding 2 hydroxymethylene 17,20;20,21 bismethylenedioxyhydrocortisone derivative ('III). The last named compound is treated with a suitable dehydrogenating agent, preferably 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a suitable solvent such as dioxane at room temperature for a period of time of the order of two minutes, thus affording the respective 2-formyl-17,20;20,2l-bismethylenedioxy A -pregnadiene derivative (IV). Conventional hydrolysis of this compound in an acid medium such as 60% formic acid yields the corresponding 2-formy-l-A -pregnadiene 11B,17ct,21 triol 3,20 dione derivative (V; R =H). Conventional acylation of this compound in pyridine with an acylating agent, as for example, acetic anhydride, furnishes the corresponding acylate of the last named compound (V; R =acyl). Dehydration of this derivative with a suitable agent, such as mesyl chloride in dimethylformamide-pyridine yields the respective 2- formyl-A -pregnatriene-17u,21-diol-3,20-dione compound (VI; R =acyl). Treatment of this compound with N-bromoacetamide in the presence of a mild acid such as perchloric acid affords the corresponding 2-formyl-9abromo-A -pregnadiened 1B,17a,21-triol-3,20-dione derivative which upon reaction in a mild basic medium, preferably potassium acetate in acetone, furnishes the respective 2-formyl-9fl,ll,B-oxido-A -pregnadiene compound. The opening of the 95,11fi-oxide ring with hydrogen fluoride or hydrogen chloride leads to the formation of the corresponding 9ot-flUO1O or chloro-l 1,8-hydroxy compound (VI I; R' acyl). Oxidation of the llli-hydroxyl of this 9tx-ha-lo derivative and of the 11,8-hydroxy 9tx-unsubstituted derivative (V; R =acyl), preferably with chromium trioxide in pyridine furnishes the correspondingl l-ketones (VIII and IX; R -=acyl).

Conventional saponification of the aboveobtained acylates of the llfi-hydroxy and ll-keto compounds (V, VII, VIII, IX; R =acyl) with potassium hydroxide, yields the respective free alcohols (V, VII, VIII, IX; R =H).

Where in the above compounds R is hydroxy, acylation at C-21 and C-16 occurs simultaneously and saponification of the-diacylates yields the respective 16ot,21-diols.

Subsequent conventional acylation of these alcohols in pyridine with a suitable acylating agent such as an anhydride of a hydrocarbon carboxylic acid of the type described previously furnishes the corresponding acylates (V, VII, VIII, IX; R =acyl) wherein the acyl group may be other than the group previously saponified.

The 1601,17oc-kfit011id6 derivatives of the present invention are prepared by the process illustrated by the following equation:

(XII) In the above formula X, Y, Z, R R and R have the same meaning as previously set forth.

In practicing the process just outlined, the starting compound which is a 2-formyl-loot-hydroxy-A -cortisone derivative (X) is condensed with a ketone, as for example acetone, methyl ethyl ketone, cyclohexanone or acetophenone, in the presence of a mild acid such as per chloric acid to give the corresponding 16a,17a-methylenedioxy derivative (XI). This compound upon conventional acylation in pyridine with an acylating agent, such as an anhydride of a hydrocarbon carboxylic acid ing ZI-acylate (XII; R =acyl The following examples serve, to illustrate but are not intended to limit this invention:

Example I Starting compounds MR Git-chloro-l7,20;20,21-bismethylcnedioxy-A -pregnen-11/9-ol-3-one.

17,20;20,21-bismethylenedioxy- N-prcgnen-l1B-0l-3-0n0.

Products fia-fluoro-M-pregnene-l 118,160:

l7a,21-tetrol-3,20-dione.

Ga-ChIOIO-h ydroeortisone hydrocortisone Example 11 benzene, there was added 3 cc. of ethyl formate and 1.3 g. of sodium hydride, suspended in mineral oil while cooling and stirring under an atmosphere of nitrogen. The mixture was stirred for 24 hours at room temperature, hexane was added until complete precipitation, the solid was collected and dried under vacuum. The crude material was suspended in dilute aqueous hydrochloric acid and stirred at room temperature for half an hour. The precipitate was collected, Washed with water and dried.

Recrystallization from methylene chloride-hexane gave .2 hydroxymethylene 6a,l6B-dimethyl-17,20;20,2l-b ismethylenedioxy-A -pregnen-1 1 p-ol-El-one.

The starting compounds listed below were treated following the above procedure, thus furnishing the corresponding products hereinafter set forth:

Starting compounds Products lfia-methyl-tta-ch1oro-17,20;20,21-

bismethylenedioxy-A -pregnen- 115-01-3-0ne.

one. 17,20;20,21-bismethylenedioxy- N-pregnen-llfi-ol-3-one.

one.

2-hydroxymethylene-1613-rnethyl- (Swfluoro-IZQO;20,2l-bismethylenedioxy-A pregnen-l-01-3- one.

2-hydr0xymethylene-Sa-ehloro- 17,20;20,21-bismethylenedioxy- A -pregnene-llfl,16a-diol-3-one.

2-hydroxymethylene-Ga-chloro- 17 ,20;20,21-bismethylenediow- A -pregnen-11B-ol-3-one.

2-hydroxyrnethylene-173020,21-

bismethylenedioxy-A -pregnen- 11B-o1-3-one.

Example 111 A mixture of 2 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in cc. of dioxane was added to a solution of 2 g. of 2-hydroxymethylene-6a,16fi-dimethyl-17,20;20,21- bismethylenedioxy-M-pregnen-1lfi-ol-3-one in 30 cc. of dioxide at room temperature. After 2 minutes at room temperature, the reaction mixture was diluted with 150 cc. of methylene chloride and then filtered to remove the precipitate of dichlorodicyanohydroquinone. The filtrate was adsorbed onto 80 g. of alumina. Elution and crystallization of the solid portions from acetone-hexane afforded 2 formyl 6u,l6,8 dimethyl 17,20;20,21 bismethylenedioxy-A -pregnadien-113-01-3 -one.

When applying the above technique to the starting compounds listed below, there were obtained the corresponding products hereinafter set forth:

Starting compounds Products one. Z-hydroxymethylene-Ga-fluoro- 17,20;20,21-bismethy1enedioxy- A -pregnene-11B,16a-diol-3-one. 2-11ydroxymethylene-Ga-chloro- 17,20;20,21-bisrnethylenedioxy- A -pregnenedlfi,16a'diol-3-one. 2-hydroxyrnethylene-Ga-ohloro- 17,20;20,21-bismethylenedioxy- A -pregnen-11B-o1-3-one. 2-hydr0xymethylene1720;20,21-

bismethylenedioxy-A -pregnen- 116-01-3-one.

2-formyl-16umethyl-6a-chloro- 17,20;20,21-bisrnethy1enediory- A -pregnadien-11B-ol-3-one.

2-iormyl-6a-chloro-17,20;20,21-

bismethylenedio xy-A -pregnadiene-11fi,16a-diol-3-one.

2-formy1-6a-ch1oro-17,20;20,21-

bisrneth ylenedioxy-A -pregnadien-11B-o1-3-one.

2-formy1-17,20;20,21-bisrnethylenedioxy-A -pregnadien-llfio1-3-one.

Example I V 1 g. of 2-formy1-6u,16,8-dimethyl-17,20;20,2l-bismethyl- 6 enedioxy-A -pregnadien-11 8-ol-3-one was heated on the steam bath with 20 cc. of formic acid for 30 minutes, cooled, diluted with water and the precipitate was collected, washed with Water, dried and recrystallized from acetone-hexane, thus affording 2-forrnyl-6a,16[3-dimethyl- A -pregnadiene-1 1B, 170:,2 l-triol-3 ,20-dione.

The starting compounds listed below were treated by the above described technique furnishing the corresponding products disclosed hereinafter:

Starting compounds Products 2-l'ormy1-16a-methylta-fluoro- 17,20;20,2l-bismethylenedioxy- A -pregnadien-11B-ol-3Fone. 2-tormyl-16a-methyl-6a-chloro- 17,20;20,21-bisrnethylenedioxy- A -pregnadien-l1/3-ol-3-one. 2-formyl-l6fl-methyl-6a-fiuorol7,20;20,21-bisrnethylenedioxy- A -ptognadien1lB-ol-3one. 2-formy1-6a-fluorod7,20;20,21-

bismethylenedioxy-A pregnadiene-llB,16a-diol-20-one. 2-formyl-6u-ch1oro-17,20;20,2l-

bismethylen edioxy-A pregnadiene-llfl,16a-diol-3-onc. 2-forrny1-6momma-17,20;20,21-

bismethylenedioxy-A -pregnadien-llfi-ol-ZS-one. 2-forrnyl-17,20;20,21-bismethy1- enedioxy-A -pregnadien-llfl- 01-3-0110.

2-formyl-6a-chloro-A -pregnadiene- 115,16a,17u,21-tetrol-3,20-dione.

2-forrnyHSvz-chloro-A -preg-nadiene-l113,17a,2l-triol-3,20-dione.

2'formyl-A -pregnadiene-llfi;

17a,21-triol-3,20-dione.

Example V Starting compounds Products 2-for-myl-lGa-mcthyl-Ga-fiuoro- A -pregnadiene-l18,17a-21- trial-3,20-dione. 2-formyl-16a-ruethyl-(ia-chloro- A -pregnadiene-l16,1701-21- triol-3,20-dione. 2-iormy1-lGfl-rncthyl-6a-fluoro- A -prognadicne-llfl,1704,21- triol-3,20-dione. 2-formyl-6mfiuoro-A -pregnadiene- 11,8,16a,17a,2l-tetrol-3,20-dione.

2-formy1-A -pregnadiene-llfidh,

21-triol-3,20-dione.

2-forrnyl-1fia-mcthyl-fia-fiuoro- A -pregnadiene-11B,170:,21- triol-B,20-dione-2Lacetate. 2-lormy1-16a-methyl-6a-chloro- A -pregnadiene-11fi,1701,21- triol-3,20-dione-21-acetate. 2-fonnyl-1GB-methyI-Ga-fiuoro- A pregnadiene-H6,17a,2ltriol-3,2Odi0ne-21-acetate. 2-formy1-6a-fluoro-A -pregna- (liene-11B,16a,l7a,21-tetro1-3,20- dione-16a,21-diaeetate. z-formyl-oa-ehloro-A -pregnadiene-l1B,1Ga,17a,21-tetrol- 3-20-dione-16a,21-diacetate. Z-IoImyl-Ga-chloro-A -pregnadien-llflJ7a,21-triol-3,20- dione-Zl-acetate. 2-formyl-A -pregnad tone-118,170,

2l-triol-3,20-dione-2l-acetate.

Example VI 1 g. of 2-formyl-6a,16 8-dimethyl-A -pregnadiene-l1B, I

17a,21-triol-3,20-dione was dissolved with slow heating in 12.5 cc. of dimethylformamide, the mixture was cooled,

0.42 g. of mesyl chloride and 0.5 cc. of pyridine were added and the solution was kept at 80 C. for half an hour. The reaction mixture was cooled, water was added and the product was extracted with ethyl acetate. The

extract was Washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. Recrystallization of the residue from acetone-hexane furnished 2 formyl 604,165 dimethyl A pregnatrien- 17,21-di0l-3,20-dione-2l-acetate.

When applying the above procedure to the starting com- Starting compounds Products Example VII 2.8 g. of N-bromoacetamide were added to a mixture of g. of 2-formyl-6cc,l6fl-dimethyl-A -pregnatriene- 17ot,2l-diol-3,20-dione-2l-acetate (obtained according to Example VI), 50 cc. of pure dioxane and 0.8 cc. of 0.4 N perchloric acid while stirring in the dark and at room temperature during 1 hour. The reaction mixture was stirred for 1 hour further, a solution of sodium sulfite was then added until the potassium starch indicator paper no longer turned blue, ice was added, the mixture was extracted with chloroform and the extract was washed consecutively with Water, 5% sodium bicarbonate solution and water, and the solvent was removed by distillation under vacuo. By trituration of the residue with acetone, there was obtained the corresponding 9ot-bromo11-hy- 'droxy derivative of the starting compound.

A mixture of 2 g. of anhydrous potassium acetate and cc. of acetone was heated almost to boiling and then a. solution of 1.7 g. of the bromohydrin in 20 cc. of acetone was added slowly while stirring; the mixture was then refluxed for 10 hours, cooled and almost all of the acetone was distilled off; iced-water was then added, the precipitate was filtered, Washed with water and dried. Upon recrystallization from methylene chloride-hexane, there was obtained 2 formyl 60:,165 dimethyl 9,8,115 oxido- A -pregnadiene-17ot,2l-diol-3,20-dione-2l-acetate.

When applying the above technique to the starting compounds listed below, there were obtained the products hereinafter disclosed:

Starting compounds Products 17a, 21-diol-3, 20-dione-2l-acetate.

17a, 21-diol-3, 20-dione-21-acetate.

1701, 2l-diol-3, 20dione-2l-acctate.

Example VIII 8 cooled in a Dry-Ice acetone bath (-70 C.) was added over a period of 20 minutes with constant stirring. The mixture was stirred at a temperature lower than 10 C. for 6 additional hours, then neutralized by cautiously adding a 5% aqueous sodium bicarbonate solution and transferred to a separatory funnel. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated until formation of an abundant precipitate. The mixture was cooled, the precipitate filtered andredissolved in hot ethyl acetate, the insoluble material was filtered oif and the filtrate cooled whereby 2-formyl- 6cc,l6fi dimethyl c fiuoro A pregnadiene llfi,

l7a,21-triol-3,20-dione-2l-acetate crystallized.

Following the above described procedure, there were treated the hereinafter indicated starting compounds, furnishing the corresponding products disclosed below:

Starting compounds Products Example IX To a solution of 4 g. of 2-formyl-6a,16 3-dimethylwater, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from acetone-hexane gave 2-formyl-6ot,16B-dimethyl 9a chloro A pregnadiene 115,111,21- triol-3,20-dione-2l-acetate.

Upon treatment by the same procedure of the starting compounds listed below, there were obtained the corresponding products hereinafter disclosed:

Starting compounds Products Example X A solution of 3 g. of 2-formyl-6a,16fi-din1ethyl-A pregnadiene-l1B,17a,21-triol-3,20-dione-2l acetate (obtained according to Example V) in 60 cc. of pyridine was added to a mixture of 3 g. of chromic trioxide in 60 cc. of pyridine. The reaction mixture was kept at room temperature overnight.

It was then diluted with ethyl acetate,

filtered through celite and the filtrate washed well With water, dried and evaporated to dryness. Crystallization from acetone-hexane afforded 2-forrnyl-6a,16,8-dimethyl- A -pregnadiene-17a,21-diol-3,1 1,20-trione-21-acetate.

When applying the above described procedure to the starting compounds listed below, there were obtained the corresponding products hereinafter set forth:

Starting compounds Products 2-forn1yl-6a,IGfi-dimethyI-Qa- 2-formyl-6a,lfifl-dimcthyl-Qachloro-A -pregnadiene-11fl,17a,- chloro-A -pregnadiene-U 01,21- 21-tri0l-3,20-dione21-acetate. dial-3,1l-20,trione-21-acetate.

Example X I 2 g. of 2 formyl 6a,16fi-dimethyl-A -pregnadiene- 17a,21-diol-3.11,20-trione-21-acetate was dissolved in 50 cc. of methanol and treated With cc. of a 4% aqueous solution of potassium hydroxide; the reaction mixture was .stirred for 1 hour under an atomsphere of nitrogen at 0 C.; the mixture was neutralized with acetic acid and the methanol distilled under reduced pressure.

The residue was triturated with water and the solid collected, washed Starting compounds Products 2-formyl-A -pregnadiene-17a, 1-

dial-3,11,20-trione. 2-1'0rmyl-16a-methyl-6a,9a-difiuoro- A -pregnadicne-17 01,21-di0l- 3,11,2D-trione. 2-formyl-lfia-methyl-fia-ehloroafluoro-A -pregnadiene-17a,21- dio1-3,11,20-trione. 2-formyl-16B-methy1-6a,9a-difluore-A -pregnadienc-17a, l-diol- 3,11,20-tri011e. Z-fOImyl-Ga,Qcr-dlfillOlO-A pregnadiene-16a,17a,21-tri0l-3,11,20- trione. 2-formyl-6a-chloro-9a-fluoro-A pregnadicne-lfia, 17a, 21-triol-3, 11, 20-tri0ne. 2-formy1-6a-chlor0-9a-fiuoro-A preguadiene-Ua, 21-diol-3, 11, 20-trione. Z-formyl-Qa-fluoro-A pregnadime-17a, 21-di0l-3, 11, 20-trione.

Starting compounds Pro duets 1Ga,17a-(methy1 phenyl methylenedioxy)-2-iormyl-6a,9a-diehloro-A -pregnadien-21-0l- 3,11,20-trione.

16a,17a-(methy1 phenyl methylenedioxy) 2-iorrnyl-6a-flu0ro- A -pregnadiene-l1 9,21-diol-3,2O- dione.

IMAM-(methyl phenyl methylenedioxy) -2-f0rmyl-6a-ch loro- A -pregnadiene,11B,2l-di01-3,20- dione.

Example XVII Following the procedure described in Example XII, except that propionic anhydride was substituted by acetic anhydride and benzoyl chloride, there were treated the starting compounds set forth in Example XVI, thus furnishing the corresponding Zl-acetates, Zl-caproates, 21- cyclopentylpropionates and 21-benzoates thereof.

We claim:

1. A compound of the following formula:

wherein X is selected from the group consisting of B-hydroxy and keto; Y is a member of the group consisting of hydrogen, fluorine and chlorine; Z is selected from the group consisting of hydrogen, fluorine, chlorine and methyl; and R is selected from the group consisting of hydrogen, oc-IllBthYl, fi-methyl, ot-hYdl'OXY and tat-hydrocarbon carboxylic acyloxy of less then 12 carbon atoms; and R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

2. 2 formyl-A -pregnadiene-11fl,l7a,21-triol-3,2O-dione.

3. 2 formyl 60,16fl dimethyl-A -pregnadiene-1 113, 17a,21-triol-3,20-dione.

4. 2 formyl 16oz methyl-6ot-fluoro-A -pregnadienel 1B,17 x,21-triol-3,2()-dione.

5. 2 formyl 165 methyl-6a-fluo1'o-A -pregnadiene- 11,3,17a,21-triol-3,20-dione.

6. 2 formyl 9a fluoro-A -pregnadiene-ll {3-17a,21- triol-3,20-dione.

7. 2 formyl 6a-9a-difiuoro-A -pregnadiene-1 15,1611, 17a,21-tetrol-3,20-dione.

8. 2 formyl-6a-chloro-9a-fluoro-A -pregnadiene-11,8, 17a,21-triol-3,20-dione.

9. 2 formyl l6a-methy1-6a,9u-diflu0ro-A regnadiene-11p,17a,21-triol-3,20-dione.

10. 2 formyl A pregnadiene-l7a,21-diol-3,11,20- trione.

11. 2 formyl ,l6fi-dimethyl-A -pregnadiene-17a, 2l-diol-3,11,20-trione.

12. 2 formyl 16u-methyl-6u-fluoro-A -pregnadiene- 17a,21-dlOl-3,11,20-1110113.

13. 2 formyl 16fl-methyl-6a-fluoro-A -pregnadiene- 17a,21-dio1-3,11,20-trione.

14. 2 formyl-9a-fluoro-A -pregnadiene-17u,2l-diol-3, 11,20-trione.

15. 2 formyl-6a,9a-difluoro-A -pregnadiene-16a,17a, 21-triol-3,1 1,20-trione.

16. 2 formyl 6a ch1oro-9a-fiuoro-A -pregnadiene- 17 a,21-di0l3,1 1,20-trione.

17. 2 formyl-16a-methyl-6a,9a-difluoro-A -pregnadiene-17a,2l-diol-3,11,20-tri0ne.

18. 2 formyl-16B-methyl-6a,9a-difluoro-A -pregnadiene-17u,21-dio1-3,11,20-trione.

19. A compound of the following formula:

(DI-R wherein X is selected from the group consisting of B-hydroxy and keto; Y is a member of the group consisting of hydrogen, fluorine and chlorine; Z is selected from the group consisting of hydrogen, fluorine, chlorine and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms and R and R are hydrocarbon radicals of up to 8 carbon atoms.

20. A process for the production of 2-formyl-A -pregnadien-3-one derivatives which comprises treating the corresponding 2-hydroxymethylene-A -pregnen-3-one compound with a dehydrogenating agent in an inert organic solvent at room temperature for a period of time of 1 to 10 minutes.

21. The process of claim 20 wherein the dehydrogenating agent is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and the solvent is dioxane.

No references cited.

l 4 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION March 10, 1964 Patent No 3,124,573

l Albert Bowers et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, lines 30 to 45, the formula should appe shown below instead of as in the patent 2' I Signed and sealed this 14th day of July 1964. v

(SEAL) Attest: a.

f EDWARD. J; BRENNER ESTION G JOHNSON Attesting Officer Commissioner of Patents f 

19. A COMPOUND OF THE FOLLOWING FORMULA: 